Interdialytic home systolic blood pressure variability increases all‐cause mortality in hemodialysis patients

Abstract Background The association between Interdialytic home blood pressure variability (BPV) and the prognosis of patients undergoing maintenance hemodialysis (MHD) largely unknown. Hypothesis We proposed the hypothesis that interdialytic home BPV exert effect on cardiac and all‐cause mortality among individuals undergoing MHD. Methods A total of 158 patients receiving MHD at the hemodialysis unit of Wuhan Fourth Hospital between December 2019 and August 2020 were included in this prospective cohort study. Patients were divided into tertiles according to the systolic BPV (SBPV), and the primary endpoints were cardiac and all‐cause death. Kaplan–Meier analysis was used to assess the relationship between long‐term survival and interdialytic home SBPV. In addition, Cox proportional hazards regression models were used to identify risk factors contributing to poor prognosis. Results The risk of cardiac death and all‐cause death was gradually increased in patients according to tertiles of SBPV (3.5% vs. 14.8% vs. 19.2%, p for trend = .021; and 11.5% vs. 27.8% vs. 44.2%, p for trend <.001). The Cox regression analysis revealed that compared to Tertile 1, the hazard ratios for all‐cause mortality in Tertile 2 and Tertile 3 were 3.13 (p = .026) and 3.24 (p = .021), respectively, after adjustment for a series of covariates. Conclusions The findings revealed a positive correlation between increased interdialytic home SBPV and elevated mortality risk in patients with MHD.


| BACKGROUND
The global prevalence of chronic kidney disease (CKD) is estimated to be 13.4%. 1 End-stage kidney disease (ESKD) is the most severe stage of disease progression, with approximately 3 million patients worldwide currently receiving dialysis.Over the past 20 years, the number of dialysis patients in developed nations has increased at an annual rate of 6%-12%, with even higher growth rates observed in developing countries, where hemodialysis is the primary form of kidney replacement therapy, accounting for more than 90%. 2,3Furthermore, the prevalence of cardiovascular disease in hemodialysis patients exceeds 60%, accounting for more than 50% of deaths. 4Hypertension is common in hemodialysis patients with a prevalence of 90%. 5 Elevated blood pressure can lead to endothelial dysfunction, atherosclerosis, and structural changes in the heart and brain, all of which increase the risk of death.In the general population, the risk of adverse cardiovascular events increases linearly with increasing systolic blood pressure. 6Nevertheless, the effect of blood pressure on the prognosis of patients with MHD is more complicated, as blood pressure can influence patient prognosis, irrespective of predialysis， interdialytic，or after dialysis, abnormal blood pressure levels, whether excessively high or low, are significantly correlated with an increased risk of cardiovascular and cerebrovascular adverse events, as well as all-cause mortality. 7Despite well-controlled mean blood pressure, high variability, and paroxysmal hypertension during visits still significantly increase the risk of cardiovascular adverse events, this illustrated that the prognosis of patients with MHD is not only dependent on the level of blood pressure but also correlated with BPV. 8 Recently, BPV has been acknowledged as an independent cardiovascular risk factor in the general population and in patients with hypertension. 9For instance, Nardin and colleagues demonstrated that both short-term and long-term increased BPV are associated with an elevated risk of cardiovascular events and allcause mortality, this conclusion also applies to hemodialysis patients, as increased BPV during both the intradialytic and interdialytic measurements yield similar results. 10,113][14] However, there exists a few reports on the association between interdialytic home BPV and the prognosis of patients undergoing MHD.Therefore, we conducted a prospective study to investigate the impact of interdialysis home BPV on the outcomes in MHD patients.

| Study methods
Before the study, all patients underwent training to correctly measure blood pressure.All patients used a corrected electronic sphygmomanometer to measure brachial artery blood pressure; blood pressure was recorded four times a day for a week on a nondialysis day, before breakfast (7:00-8:30), before lunch (10:30-12:00), before dinner (17:00-19:00), and before going to bed.Patients taking antihypertensive medication were asked to measure their blood pressure before taking the medication.The BPV coefficient of variance (CV) was calculated as CV = (standard deviation/mean) × 100%.Both the systolic and diastolic BPV and mean blood pressure were calculated according to the blood pressure measured several times.Bioelectrical impedance analysis-based body composition analysis were used for assessing fuid volume and nutritional status in MHD patients.Body composition was performed using multifrequency electric bioimpedance (model InBody S10，Biospace Co., Ltd.) immediately after hemodialysis.
In addition, baseline data, including gender and age, dialysis vintage, vascular access, dialysis prescription, primary kidney disease, history of ischaemic heart disease was detected by reviewing medical records for confirmation or asking patients directly-which included angina, myocardial infarction, or exist other evidence of ischaemic heart disease, such as coronary angiography results shows vascular stenosis, smoking history, hemoglobin, serum albumin (ALB), creatinine, urea nitrogen, triglycerides, total cholesterol (TC), parathyroid hormone (PTH), calcium, phosphorus, serum uric acid, and bioelectrical impedance, were collected.

| Endpoints
The patients were followed using outpatient follow-up, telephone communication, and in-patient medical record inquiry.They were followed up until April 30, 2023.The endpoints were cardiac death (including myocardial infarction, malignant arrhythmia, and heart failure), all-cause death, or termination of follow-up.This study was approved by the Ethics Committee of the Wuhan Fourth Hospital (No. KY2022-046-01) in accordance with the Declaration of Helsinki and authorized by Medical Ethics.

| Statistical analysis
Continuous variables conforming to the normal distribution are denoted by mean ± standard deviation (SD).Non-normally distributed continuous variables are denoted by interquartile ranges (IQR), and counting data are expressed as frequency and percentage.Left ventricular ejection fraction (LVEF) is described with the minimum, maximum, and median values.The t test was used to compare the measurement data between two groups subjected to normal distribution, whereas the Mann-Whitney U or Kruskal-Wallis H test was used to compare between two or more groups without a normal distribution.The χ 2 test was used to compare the categorical data between groups.A restricted cubic spline risk curve was used to describe the association between elevated levels of systolic blood pressure variability (SBPV) and the risk of outcome events.Kaplan-Meier survival curves and Log-rank tests were used to compare the differences in survival among tertiles.Univariate Cox regression analysis was used to identify variables affecting the occurrence of all-cause mortality among patients, and subsequently, significant variables were included in multivariate Cox regression analysis to ascertain the effect of SBPV on cardiovascular death and all-cause mortality.All statistical tests were performed by two-sided test, and p < .05 was considered statistically significant.Statistical analyses were performed using R version 3.6.0and SPSS 26.0.Photoshop version 6.0 were used for graphs.

| Basic characteristics of patients
A total of 158 patients were included in the study, consisting of 95 males (60.1%) and 63 females (39.9%).The age of patients varied from 25 to 88 years old, with an average age of 57 ± 13 years old.
Arteriovenous fistulas (AVF) were selected for vascular access for hemodialysis in 117 (74.1%) patients, and tunneled cuffed catheter was selected in 41 (25.9%) patients.In total, 35 (22.2%) patients underwent hemodialysis twice a week, 21 (13.3%)patients five times every 2 weeks, and 102 (64.6%) patients received hemodialysis thrice a week.The shortest and longest dialysis vintages varied from 9 months to 207 months.The shortest follow-up was for 4 months, the longest was for 40 months, and the median follow-up was 33 months; among the patients, 44 deaths occurred during the follow-up period.Twenty deaths were attributed to cardiovascular causes, including 1 who had sudden cardiac death, 10 died of congestive heart failure, and 9 who had ischemic heart disease.

| Relationship between BPV and patient outcomes
To assess the effect of BPV on long-term outcomes, a restricted cubic spline model was employed to analyze the data.The results revealed that an increase in SBPV within a specific range was associated with a higher risk of cardiac death and all-cause death (Figure 1A,B).Conversely, no similar trend was observed for DBPV.Therefore, patients were divided into tertiles according to the SBPV, and significant differences were observed among tertiles when comparing the baseline data (Table 1  In terms of clinical outcomes, patients in Tertile 2 and Tertile 3 exhibited a progressive increase in both cardiac death and all-cause death when compared to those in Tertile 1 (3.5% vs. 14.8% vs. 19.2%,p for trend = .021,and 11.5% vs. 27.8% vs. 44.2%,p for trend <.001) (Figure 2).The Kaplan-Meier survival analysis demonstrated a significant difference in cumulative survival between Tertile 1, Tertile 2, and Tertile 3, and the higher SBPV associated with an increased risk of cardiac death (Log-rank test χ 2 = 6.372, p = .041)and all-cause death (Log-rank test χ 2 = 12.677, p = .002)(Figure 3A,B).
As age increases, BPV increases accordingly.To compare the possible effects of BPV in different age groups, we grouped patients at the age of 60-year-old for comparison (Supporting Information S1: Table 5).Univariate Cox regression analysis revealed that gender, serum albumin, serum phosphorus, diastolic BP, pulse pressure, DBPV, age, diabetes, ECW/TBW, and PA were associated with death (Supporting Information S1: Table 6).Furthermore, patients in Tertile 2 and Tertile 3 exhibited a significantly higher risk of cardiac death and all-cause death compared to those in Tertile 1 (p < .05).Thus, after adjusting for different variables and building different models, we found that the risk of all-cause death was still significantly higher in Tertile 2 and Tertile 3 compared with Tertile 1.Although this trend was not significant in the risk of cardiac death, we found that the SBPV increased with an increase in the risk of death (Table 2).

| DISCUSSION
In this prospective cohort study, the prevalence of hypertension among patients with MHD was found to be 92.4%,significantly higher than that in the general population.The risk of cardiac and all-cause mortality was significantly higher in patients with high home SBPV, this result was similar to those of previous studies, 15 while the present study found there is no U-shaped curve relationship between home SBPV and adverse outcomes.[18][19] Undergoing hemodialysis two to three times a week leads to significant fluctuations in blood pressure in MHD patients.The KDOQI and the Canadian Society of Nephrology recommend using pre-and postdialysis BP measurements to guide hypertension management; however, studies have found a stronger correlation between home blood pressure and poor prognosis in MHD patients, [20][21][22] but no clear conclusion about effect of home BPV on MHD patients prognosis has been reached.The majority of current studies on BPV calculation in hemodialysis patients primarily depend on office and intradialytic blood pressure; our present prospective study has clarified the association between home BPV and poor prognosis.
BPV reflects the degree of fluctuation in blood pressure over time.BPV can be divided into short-term, medium-term, and longterm variations.Short-term variation usually refers to BPV within 24 h, which can be divided into BPV during the cardiac cycle, BPV within a few minutes or hours, and circadian rhythm changes.In contrast, long-term BP variability primarily includes day-to-day, visitto-visit, or seasonal BP variability.Compared with short-term BPV, long-term BPV has better reproducibility and less random variability. 23,24In the present study, we selected interdialytic home BPV for a week on nondialysis days belongs to long-term BPV.Currently, there exists no widely accepted measure of BPV, which is usually expressed as standard deviation, coefficient of variation, average real variability (ARV), and variation independent of the mean (VIM).

Compared with the standard deviation, the coefficient of variation F I G U R E 1 Restricted cubic spline curves of the risk for cardiovascular mortality (A) and all-cause death (B).
T A B L E 1 Baseline characteristics of study population by tertiles of interdialysis home systolic blood pressure variability.can overcome the effect of mean blood pressure on BPV, does not consider the sequence of blood pressure measurements, and is easy to calculate clinically.Although VIM and ARV can respond to fluctuations independent of mean BP, the calculations are complex and difficult to generalize in clinical practice.Rossignol and colleagues reported that the CV of blood pressure was the most appropriate to measure BPV in patients with MHD. 25 In addition, long-term monitoring of BPV depends on accurate, repeatable blood pressure measurements.Home blood pressure monitoring can provide multiple blood pressure readings in an individual's daily environment, avoiding white coats and masked hypertension.Moreover, the affordable, long-term use of the method is easily accepted by patients and is the best method for long-term follow-up of patients with hypertension. 13,26Therefore, this study demonstrated that home blood pressure CV can better predict long-term adverse events in patients.
8][29] In hemodialysis patients, several diseases often coexist, and the body is in a state of chronic microinflammation for a prolonged time.Although the metabolic substances, vasoactive mediators, and water accumulated during hemodialysis are removed, severe changes in hemodynamics and internal environment in a short time cause significant fluctuations in blood pressure.Consistent with previous studies, we found higher BPV in older patients with diabetes. 30In addition, we found that outcomes derived from bioelectrical impedance revealed a correlation between increased visceral fat content and body fat percentage, diminished muscle content and phase angle, and heightened BPV.
5][36] Kato and colleagues reported a significant negative correlation between the thigh muscle area and carotid intima-media thickness, cardio-malleolus vascular index, and ankle-brachial index in patients with MHD. 37Previous F I G U R E 2 Percentage of cardiovascular and all-cause mortality in tertiles of interdialysis home systolic blood pressure variability.
studies have demonstrated an independent association between PA and nutritional and inflammatory markers in patients with uremia, with a smaller PA, indicating a higher severity of atherosclerosis and vascular calcification. 38mpared to average blood pressure, BPV exerts a more pronounced impact on the damage inflicted by hypertension on target organs.Elevated BPV signifies greater fluctuations and consequently a heightened susceptibility to cardiovascular and cerebrovascular diseases. 39A meta-analysis revealed that with each 1 mmHg increase in the standard deviation of systolic blood pressure, the likelihood of all-cause mortality increased by 3%, cardiovascular death by 10%, and stroke by 2%. 40The mechanism underlying blood pressure fluctuations contributing to target organ damage and adverse events remains elusive; it could be associated with increased arterial stiffness, remodeling of the microcirculation, inflammatory response, activation of the sympathetic nervous system, and RASS, and so forth. 41Our findings indicated that, when SBPV was less than 10%, there was a gradual increase in the risk of cardiac death and all-cause death as the variability increased.However, when the SBPV exceeded 10%, the relationship between SBPV and adverse events became less apparent.Also, we found that the risk of all-cause death was higher in Tertile 3 than in Tertile 2 (3.24 vs. 3.13), this trend was not observed in cardiac death (5.58 vs. 4.72).We think this unexpected finding may be due to the small sample size and short follow-up time, and further investigation with long-term followup is warranted to confirm these findings.
Additional reductions in blood pressure variability are beneficial in improving patient outcomes.Limited evidence suggests that the administration of calcium channel blockers, controlled fluid intake, and decreased ultrafiltration volume could contribute to the reduction of BPV in patients with MHD.Conversely, the use of antihypertensive regimens containing β-blockers and RAAS system inhibitors is not beneficial in improving interdialysis BPV in dialysis patients. 18,19,42e study had certain limitations.First, home blood pressure measurement could not evaluate the fluctuations in blood pressure during sleep; we were unable to compare predialysis BP variability, postdialysis BP variability, and home BP variability simultaneously.Second, although we analyzed the effect of antihypertensive drug use on outcomes in each group, we were unable to assess compliance; we are also unable to accurately evaluate the impact of other factors on blood pressure variability.
Third, the trend of home BP variability on cardiac death is not particularly significant, long follow-up duration, more multicenter and large sample-size studies are warranted to confirm these findings.Lastly, our study solely focused on assessing the correlation between the coefficient of variation and adverse outcome events, without analyzing the effects of other measures such as standard deviation, ARV, and VIM.
In conclusion, our findings suggest that higher home SBPV is linked to increased risks of all-cause death and cardiac death among hemodialysis patients.Reducing home SBPV could improve patients' long-term prognosis.
This single-center prospective cohort study was designed to assess the impact of home BPV on the survival outcomes in patients with MHD.Patients with ESKD who underwent MHD in the hemodialysis unit of Wuhan Fourth Hospital from December 2019 to August 2020 were selected and informed consent was obtained.Inclusion criteria were (1) age ≥18 years, (2) dialysis vintage ≥3 months, (3) cooperation with home measurement of upper extremity blood pressure, and (4) undergoing bioelectrical impedance measurements to assess fluid load and other health indicators.Exclusion criteria were (1) patients with complicated with severe refractory heart failure (NYHA Class III-IV), (2) those who had experienced severe infection or acute cardiovascular and cerebrovascular accidents within 3 months before the study, (3) patients with severe liver disease or malignant tumor, and (4) individuals who underwent kidney transplantation or peritoneal dialysis during the follow-up.

F| 7 of 9 T A B L E 2
I G U R E 3 Kaplan-Meier survival curves and life tables for occurrence of the endpoint (A) cardiovascular mortality and all-cause death (B).DONG ET AL.Associations between tertiles of interdialysis home systolic blood pressure variability and all-cause and cardiovascular (CV) mortality.